Project Summary/Abstract Neuroscience research over the last decade has been revolutionized by many technological advancements. Optogenetics and fluorescence imaging represent two distinct, and sometimes complementary tools used in neuroscience research to study the central and peripheral nervous systems in the context of the BRAIN initiative. Advanced interrogations of underlying neural circuits and biology are often frustrated, however, by technological limitations that prevent the use of these approaches to study natural behaviors of untethered, freely moving animals. Traditional fiber-optic cable for optogenetics and bulky metal cannulas connected with external mechanical pumps for pharmacology impart significant damage to fragile neural tissue, limit the natural behavior of freely moving animals, affect social interactions and movements in complex, naturalistic 3D environment, and lead to persistent irritation at the biotic/abiotic interface due to mechanical mismatch and micromotions. These drawbacks, together with the costly setup, of current technologies motivate the development of innovative engineering designs to improve fidelity, operational ease, versatility and range of advanced brain research studies with live animal models. Our work during Phase II developed capabilities to build our existing system-level hardware and software, as well as scalable manufacturing scheme to fabricate our wireless, battery-free optogenetics devices. Through these efforts, NeuroLux has already achieved substantial success in disseminating tools for neuroscience research, increasing user base to 80 laboratories in 11 countries in the last three years. The proposed work for Phase IIB focuses on further propelling our initial success by refining critical aspects of our hardware, as well as expanding our capabilities to include fully implantable, wireless, battery-free fluorescence imaging to monitor neural activity in real time, in a manner that leverages our current hardware and software. Specifically, the proposed work will (1) develop hardware for multi-enclosure operation with advanced features, (2) advance long- range optogenetic stimulators with active, programmable control over illumination intensity, and (3) develop optoelectronic photometers with options with integrated optogenetic stimulation capabilities.